Effects of the new cardiotonic phosphodiesterase inhibitor 1,2-dihydro-5- imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3-pyridine-carbonitrile hydrochloride monohydrate on aortic input impedance

Abstract

Beneficial effects of cardiotonic phosphodiesterase inhibitors on congestive heart failure are possibly mediated in part by a reduction of afterload. 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3- pyridinecarbonitrile hydrochloride monohydrate (E-1020, CAS 119615-63-3), a new cardiotonic phosphodiesterase inhibitor was evaluated for its effect on aortic input impedance in eight anesthetized open-chest dogs. First instantaneous aortic pressure and flow under random ventricular pacing before and after E-1020 infusions (10, 30, and 100 micrograms/kg i.v.) were measured. Then aortic input impedance over the frequency range of 0.024 to 20 Hz was estimated using a multichannel autoregressive model. With the infusion of E-1020, aortic input impedance was decreased in the low frequency range (below 0.1 Hz) and shifted leftward in the transitional frequency range (from 0.1 to 2 Hz), while it remained unchanged in the high frequency range (above 2 Hz). Parameterization of the aortic input impedance using a three-element Windkessel model indicated that E-1020 (at a dose of 100 micrograms/kg i.v.) decreased arterial resistance by 35% (p less than 0.01) and increased arterial compliance by 12% (p less than 0.01). It is concluded that E-1020 improves cardiac performance by unloading static and dynamic afterload in addition to its cardiotonic effect.